Tag Archives: epileptogenesis

How to Understand Temporal Lobe Epilepsy

Pathophysiology of epilepsy, , ,

Introduction

In the previous blog (see blog 23), it was clear that not all animal models used for epilepsy research are of equal value.  Some are useful to develop antiseizure drugs.  Others, however, may uncover epileptogenesis, that is the pathological origins of epilepsy, plus the subsequent disease trajectory.  This blog focuses on one animal model of epilepsy with potential for a cure.  This is the kainic acid rodent model.  It exhibits many of the changes evident in humans with temporal lobe epilepsy.  Temporal lobe epilepsy is a common type of epilepsy.  It is generally drug-resistant.  Hence, the reason this model is a noteworthy animal model of epilepsy with potential for a cure. 

Temporal lobe epilepsy – brain site, manifestations, pathology

Location

Temporal lobe epilepsy is the general term for seizures originating from the temporal lobe.  The temporal lobe is one of several regions of the brain (see figure below).  The temporal lobes are located on either side of the brain (approximating the temples).  Temporal lobes control memory, facial recognition, language perception, and hearing.  Additionally, they have strong connections to the limbic system which affects behavior, emotion and motivation.

Symptoms

There are two subdivisions of temporal lobe epilepsy.  They are mesial temporal lobe epilepsy and lateral temporal lobe epilepsy.  The former is the most common.  Spontaneous seizures characterize temporal lobe epilepsy. They appear as a stare or automated muscle contractions and movements.  Additionally, memory loss and confusion occur post seizure.  Seizures originating from the limbic system may be preceded by an aura, strange smells/tastes or strong emotions.  Thus, specific manifestations depend on the brain region of origin.

Pathology

Data obtained in humans from a variety of sources (surgical procedures, EEGs, MRIs, autopsies) show consistent neurological damage.  Specifically, tissue injury (death/disappearance of neurons) appears in key sub regions of the temporal lobe.  Distinct structures such as the hippocampus and amygdala are clearly affected and scarred.   

Kainic Acid Animal Model 

Description

The kainic acid animal model is a rodent (mouse, rat) model.  A researcher injects kainic acid into the animal.  It is the initiator of  the development of epilepsy. This model mimics human temporal lobe epilepsy both in the underlying pathological and in seizure expression. 

Kainic acid is chemically similar to an excitatory neurotransmitter, glutamate.  Thus, kainic acid binds to a select group of glutamate receptors, concentrated in the temporal lobe and stimulates excessive electrical activity in the brain.  Within minutes to hours, severe seizures occur (termed status epilepticus).  Within days and months depending on the model protocol, chronic seizures indicative of temporal lobe epilepsy occur and persist.

As shown by extensive study results, many factors determine the exact outcome.  For example, some of these factors are a) the route of administration of kainic acid (into the abdominal cavity, directly into select brain sites, intranasal), b) the dose of  acid (and when given all at once or in small doses), c) the rodent choice (rat or mouse), d) rodent sex and age, and e) whether housed singly or in groups affect the precise seizure expression and its frequency.  However, this appears to be an asset of this model since the variety of outcomes (termed phenotype) approximates the variety of epilepsy expression in humans.

Key Mechanism

A significant change in the brain of the kainic acid model is the activation of a highly important and ubiquitous protein with the strange name of mTOR.  The name originated when this specific protein was discovered as the “mechanistic Target Of Rapamycin”.  Rapamycin (sirolimus), a well-known immunosuppressant strongly inhibits this protein.  mTOR influences just about all biological activities, e.g. metabolism, cell-cell communication, aging, cell death, protein formation, wound healing and immune function.  Additionally, mTOR in the brain influences generation and growth of neurons,  supports their well-being and enhances connections among them. 

Excessive stimulation of mTOR in the brain as in the induction of status epilepticus of the kainic acid model, and in humans following traumatic brain injury, stroke or genetic errors eventually morphs into temporal lobe epilepsy.  Rapamycin is obviously the drug of choice to block excessive activation of mTOR.  However, rapamycin exerts other effects, negatively affecting the outcome of treatment. 

Data show that undue activation of mTOR  is a reasonable cause of epilepsy.  Effort has been and continues to focus on  the role of  mTOR in epilepsy.  Specifically, it is necessary to understand just how mTOR causes neuronal cell damage and death, changes that perpetuate seizures.  Continuing research with the kainic acid model enables insights needed for an epilepsy cure.

Major Message

No animal model used to study a disease and develop a cure is perfect.  Animal brains are not human brains.  However, the kainic acid model is one of a few that has been characterized and shown to have many similarities, down to the cellular and mechanistic level, to human temporal lobe epilepsy.   Continued studies with this model have the potential to understand the epileptogenesis of seizures.  Rather than suppress seizures, the origin of seizures could be eliminated.

Brain Regions

References on request.

Especially Valuable Epilepsy Cure Advice

Current Research Advances, ,

Introduction 

Despite an extensive research effort and a wealth of available antiseizure medications, a cure for epilepsy remains elusive.  Riley and Danzer (2024) in a recent review discuss the reasons for this.  The path to a cure begins with preclinical research that focuses on the disease initiation termed epileptogenesis and its associated co-morbidities.  Epileptogenesis and disease-dependent co-morbidities, e.g. cognitive decline are key therapeutic targets for a cure.  Riley and Danzer (2024) provide especially valuable epilepsy cure advice by their critique of current preclinical models and proposed improvements.  The especially valuable epilepsy cure advice provided by these scientists is summarized below in a series of insights.

Preclinical animal model types:  acute, acquired and genetic

Especially valuable epilepsy cure advice – Insight 1 

In the development of antiseizure medications (Assessment 6 – Epilepsy Medication – Need to Know Information), the model of choice is the acutely provoked seizure model.  It is known that “acutely evoked seizures generated by normal brains, however, are mechanistically different from spontaneous seizures generated by epileptic brains” (Riley and Danzer, 2024).  Despite this, there are over 25 approved antiseizure medications. Many more are presently in clinical trials (Novel Anti-seizure Drugs – Ongoing Research). 

It is clear that antiseizure medications do not provide a cure for epilepsy.  Seizures return with drug cessation. As supported by clinical trial results, antiseizure medications have no ameliorating effects on epileptogenesis (origin of the seizure) or associated disease comorbidities e.g. cognitive decline.  Epilepsy cure advice proposes that basic preclinical research investigate ways to slow disease progression and initiate beneficial changes even when therapy is withdrawn (Riley and Danzer, 2024).  Since development of antiseizure medications will not yield a cure, a change in research focus is needed.

Especially valuable epilepsy cure advice – Insight 2 

Some of the preclinical epilepsy models are acquired epilepsy models induced by any number of traumatic brain injuries that go on to change the normal brain to an epileptic one.   These model will play an important role in finding a cure for epilepsy. 

However, in these models, it is important to distinguish between the effect of therapy on injury reduction per se and its effect on prevention of induced epileptogenesis.  Thus, determination of timing between these events is key.  Not surprisingly, early therapeutic interventions are more successful. This is because they reduce the effect of injury per se. Such therapy is obviously impractical in real life where brain injury is unpredictable.  Although the goal is epileptogenic therapy and disease modification, injury reduction in traumatic brain injury, where known, is still very important.

Especially valuable epilepsy cure advice – Insight 3 

Epilepsy is chronic.  Patients endure this disease for years.  Therefore, animal models need to be long term.   However, animal models are rarely chronic due to expense and time/labor commitment.  Yet chronic models would be the best ones to study.  Additional advantages of chronic models are many. They include the ability to obtain a baseline EEG, group animals according to similar seizure types, reduce variability and actually use fewer animals (Riley and Danzer, 2024).  Biomarkers would greatly facilitate investigations in epileptogenesis with chronic models (Engel and Pitkänen, 2020).  Sadly, there markers are still in early stages of development.

Especially valuable epilepsy cure advice – Insight 4 

Genetic models target a subset of epilepsies.  In these models, the time of expression of  abnormal gene(s) needs accurate determination to be relevant to epileptogenesis.  Additionally, long term studies with genetic models would be of considerable value.

Especially valuable epilepsy cure advice – Insight 5 

The epilepsy therapy screening program (ETSP)originated over 40 years ago. It provided essential data for many of the antiseizure medications approved by the FDA.  Historically, the ETSP has focused on identification of antiseizure medications for patients who are drug resistant. Currently, “the ETSP contract site has, for the first time, adopted a strategy to explore the potential of novel compounds to prevent epilepsy or to be disease modifying” (Wilcox et al., 2020).  The Neurological Diseases and Stroke of the National Institute of Health at the University of Utah funds and administers this program.  

Scientists now use several epilepsy models. These are an infection-induced model of temporal lobe epilepsy, genetic models and the validated KA-SE (Kainic Acid-Status Epilepticus) model. The latter produces spontaneous seizures.  The KA-SE model mimics temporal lobe epilepsy in humans both in epileptogenesis and disease progression. 

Analysis of therapies in these models has potential to achieve a cure. However, evaluation of therapies in novel etiologically relevant  models face many challenges.  These include lack of a positive control, need to develop an appropriate study design, determination of time window to treat following the brain insult, the duration of treatment and dose, and how long post treatment to observe animals.  These all remain for future evaluation but are realistically achievable.

Conclusions 

A number of researchers, notably those mentioned above and others, are providing especially valuable epilepsy cure advice.  It is important to move away from discovery of antiseizure medications that only suppress symptoms of epilepsy. These medications do nothing to prevent epileptogenesis or modify disease progression. They have failed to identify a cure for epilepsy.  Therapy testing in relevant animal models in essential to meet this goal.

References https://pubmed.ncbi.nlm.nih.gov/

1.  Riley VA, Danzer SC. Preclinical Testing Strategies for Epilepsy Therapy Development.Epilepsy Curr. 2024 Oct 25;25(1):51-57. doi: 10.1177/15357597241292197

2.  Engel J, Jr, Pitkänen A. Biomarkers for epileptogenesis and its treatment. Neuropharmacology. 2020;167:107735 doi: 10.1016/j.neuropharm.2019.107735

3.  Wilcox KS, West PJ, Metcalf CS. The current approach of the Epilepsy Therapy Screening Program contract site for identifying improved therapies for the treatment of pharmacoresistant seizures in epilepsy. Neuropharmacology. 2020;166:107811 doi: 10.1016/j.neuropharm.2019.107811